Structural Basis for VEGF-C Binding to Neuropilin-2 and Sequestration by a Soluble Splice Form
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Authors
Parker, Matthew W.Linkugel, Andrew D.
Goel, Hira Lal
Wu, Tingting
Mercurio, Arthur M.
Vander Kooi, Craig W.
UMass Chan Affiliations
Department of Molecular, Cell and Cancer BiologyDocument Type
Journal ArticlePublication Date
2015-04-07
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Vascular endothelial growth factor C (VEGF-C) is a potent lymphangiogenic cytokine that signals via the coordinated action of two cell surface receptors, Neuropilin-2 (Nrp2) and VEGFR-3. Diseases associated with both loss and gain of VEGF-C function, lymphedema and cancer, respectively, motivate studies of VEGF-C/Nrp2 binding and inhibition. Here, we demonstrate that VEGF-C binding to Nrp2 is regulated by C-terminal proteolytic maturation. The structure of the VEGF-C C terminus in complex with the ligand binding domains of Nrp2 demonstrates that a cryptic Nrp2 binding motif is released upon proteolysis, allowing specific engagement with the b1 domain of Nrp2. Based on the identified structural requirements for Nrp2 binding to VEGF-C, we hypothesized that the endogenous secreted splice form of Nrp2, s9Nrp2, may function as a selective inhibitor of VEGF-C. We find that s9Nrp2 forms a stable dimer that potently inhibits VEGF-C/Nrp2 binding and cellular signaling. These data provide critical insight into VEGF-C/Nrp2 binding and inhibition.Source
Structure. 2015 Apr 7;23(4):677-87. doi: 10.1016/j.str.2015.01.018. Epub 2015 Mar 5. Link to article on publisher's siteDOI
10.1016/j.str.2015.01.018Permanent Link to this Item
http://hdl.handle.net/20.500.14038/36515PubMed ID
25752543Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.1016/j.str.2015.01.018